7.Bruins M., et al. What is the effectiveness and harm of medical and/or nutritional
therapy on the pregnancy rate in couples with idiopathic male infertility? PROSPERO: International
prospective register of systematic reviews, 2016.

27.Ghanem, M., et al. Comparison of the outcome of
intracytoplasmic sperm injection in obstructive and non-obstructive azoospermia in the first cycle: a report
of case series and meta-analysis. Int J Androl, 2005. 28: 16.

31.Vernaeve, V., et al. Intracytoplasmic sperm injection
with testicular spermatozoa is less successful in men with nonobstructive azoospermia than in men with
obstructive azoospermia. Fertil Steril, 2003. 79: 529.

86.Zhang, F., et al. Partial deletions are associated with
an increased risk of complete deletion in AZFc: a new insight into the role of partial AZFc deletions in
male infertility. J Med Genet, 2007. 44: 437.

243.Skinner, R., et al. Recommendations for gonadotoxicity
surveillance in male childhood, adolescent, and young adult cancer survivors: a report from the
International Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the
PanCareSurFup Consortium. Lancet Oncol, 2017. 18: e75.

1.INTRODUCTION

1.1. Aim

The European Association of Urology (EAU) Guidelines Panel on Male Infertility has
prepared these Guidelines to assist urologists and healthcare professionals from related specialties
in the treatment of male infertility. Urologists are usually the initial specialty responsible for
assessing men when male infertility is suspected. However, infertility can be a multifactorial
condition requiring multidisciplinary involvement.

It must be emphasised that clinical guidelines present the best evidence available
to the experts. However following guideline recommendations will not necessarily result in the best
outcome. Guidelines can never replace clinical expertise when making treatment decisions for
individual patients, but rather help to focus decisions - also taking personal values and
preferences/individual circumstances of patients into account.Guidelines are not mandates and do not
and should not purport to be a legal standard of care.

1.2.Publication history

The EAU Male Infertility Guidelines were first published in 2001, followed by
full-text updates in 2004, 2007, 2010, 2013, 2014, 2015 and 2016. In 2017, a scoping search was
performed, covering all areas of the guideline which was updated accordingly.

1.3.Available Publications

A quick reference document (Pocket Guidelines) is available, both in print and in a
number of versions for mobile devices, presenting the main findings of the Male Infertility
Guidelines. These are abridged versions which may require consultation together with the full text
versions. The Male Infertility Panel published a number of scientific publications in the EAU
journal European Urology [1,2].
A separate scientific paper on Vasectomy was published in 2012 [2].
All texts can be viewed and downloaded from the society website: http://www.uroweb.org/guidelines/male-infertility/.

1.4.Panel composition

The Male Infertility Guidelines Panel consists of urologists, endocrinologists and
gynaecologists with special training in andrology and experience in the diagnosis and treatment of
male infertility. All experts involved in the production of this document have submitted potential
conflict of interest statements which can be viewed on the EAU website: http://www.uroweb.org/guideline/male-infertility/.

2.METHODS

2.1.Introduction

For the 2018 edition of the EAU Guidelines, the Guidelines Office have transitioned
to a modified GRADE methodology across all 20 guidelines [3,4].
For each recommendation within the guidelines, there is an accompanying online strength rating form
which addresses a number of key elements namely:

the overall quality of the evidence which exists for the recommendation, references used in this
text are graded according to a classification system modified from the Oxford Centre for
Evidence-Based Medicine Levels of Evidence [5];

the magnitude of the effect (individual or combined effects);

the certainty of the results (precision, consistency, heterogeneity and other statistical or
study related factors);

the balance between desirable and undesirable outcomes;

the impact of patient values and preferences on the intervention;

the certainty of those patient values and preferences.

These key elements are the basis which panels use to define the strength rating of
each recommendation. The strength of each recommendation is represented by the words ‘strong’ or
‘weak’ [6].
The strength of each recommendation is determined by the balance between desirable and undesirable
consequences of alternative management strategies, the quality of the evidence (including certainty
of estimates), and nature and variability of patient values and preferences. The strength rating
forms will be made available online. Additional information can be found in the general Methodology
section of this print, and online at the EAU website; http://www.uroweb.org/guideline/.

A list of Associations endorsing the EAU Guidelines can also be viewed online at
the above address. In particular, the Male Infertility Guidelines have been endorsed by the Hellenic
Society of Reproductive Medicine.

The recommendations provided in these guidelines are based on a systematic
literature search performed by the panel members. The controlled vocabulary of the MeSH database was
used alongside a free text protocol, combining “male infertility” with the terms “diagnosis”,
“epidemiology”, “investigations”, “treatment”, “spermatogenic failure”, “genetic abnormalities”,
“obstruction”, “hypogonadism”, “varicocele”, “cryptorchidism”, “testicular cancer”, “male accessory
gland infection”, “idiopathic”, “contraception”, “ejaculatory dysfunction”, and
“cryopreservation”.

For the 2018 print, a scoping search was performed, covering all areas of the
guideline, starting from the last cut-off date April 2016 with a cut-off date of May 2017. Embase,
Medline and the Cochrane Central Register of Controlled Trials databases were searched, with a
limitation to systematic reviews and meta-analysis of randomised controlled trials (RCTs). A total
of 779 unique records were identified, retrieved and screened for relevance, of which nine
publications were selected for inclusion. A detailed search strategy is available online: http://www.uroweb.org/guideline/male-infertility/.

2.2.Review

This document was subject to peer review prior to publication in 2015.

2.3.Future goals

The results of ongoing and new systematic reviews will be included in future
updates of the Male Infertility Guidelines. Ongoing systematic reviews include:

What are the benefits of nutritional and/or medical therapy on the pregnancy rate and semen
parameters and harms in males with idiopathic infertility? [7].

3.EPIDEMIOLOGY AND AETIOLOGY – GENERAL PRINCIPLES

3.1.Introduction

Definition
“Infertility is the inability of a sexually active, non-contracepting couple to
achieve spontaneous pregnancy in one year”, World Health Organization (WHO) [8].

About 15% of couples do not achieve pregnancy within one year and seek medical
treatment for infertility. One in eight couples encounter problems when attempting to conceive a first child and
one in six when attempting to conceive a subsequent child. Three percent of women remain
involuntarily childless, while 6% of parous women are not able to have as many children as they
would wish [9].
Infertility affects both men and women. In 50% of voluntarily childless couples, a
male-infertility-associated factor is found together with abnormal semen parameters. A fertile
partner may compensate for the fertility problem of the man and thus infertility usually manifests
if both partners have reduced fertility [8].
Male fertility can be impaired as a result of [8]:

congenital or acquired urogenital abnormalities;

malignancies;

urogenital tract infections;

increased scrotal temperature (e.g. as a consequence of varicocele);

endocrine disturbances;

genetic abnormalities;

immunological factors.

In 30-40% of cases, no male-infertility-associated factor is found (idiopathic male
infertility). These men present with no previous history of diseases affecting fertility and have normal findings
on physical examination and endocrine, genetic and biochemical laboratory testing. However, semen
analysis might reveal pathological findings in the spermiogram (see 4.2.1). Table 1 summarises the
main male-infertility-associated factors. Idiopathic male infertility is assumed to be caused by
several factors, including endocrine disruption as a result of environmental pollution, reactive oxygen species, or genetic and epigenetic
abnormalities.

3.2.Recommendations on epidemiology and aetiology

Examine all men
diagnosed with fertility problems, including men with abnormal semen parameters for
urogenital abnormalities.

Strong

4.PROGNOSTIC FACTORS AND DIAGNOSTIC EVALUATION -
GENERAL PRINCIPLES

4.1.Prognostic factors

Prognostic factors for male infertility are:

duration of infertility;

primary or secondary infertility;

results of semen analysis;

age and fertility status of female partner.

The cumulative pregnancy rate is 27% in infertile couples with two years of
follow-up and oligozoospermia as the primary cause of infertility [11].
Female age is the most important single variable influencing outcome in assisted reproduction [12].
Compared to a woman aged 25 years, the fertility potential of a woman aged 35 years is reduced to
50%, to 25% at 38 years, and less than 5% at over 40 years. In many Western countries, women
postpone their first pregnancy until after their education and starting a career.

4.2.Diagnostic evaluation

4.2.1.Semen analysis

A medical history and physical examination are standard assessments in all men,
including scrotal ultrasound (US) [13]
and semen analysis. A comprehensive andrological examination is indicated if semen analysis shows
abnormalities compared with reference values (Table 2). Important treatment decisions are based on
the results of semen analysis, therefore, it is essential that the complete laboratory work-up is
standardised. Ejaculate analysis has been standardised by the WHO and disseminated by publication of
the WHO Laboratory Manual for the Examination and Processing of Human Semen (5th edn.) [14].
It is the consensus that modern spermatology must follow these guidelines.

4.2.1.1.Frequency
of semen analysis

If the results of semen analysis are normal according to WHO criteria, one test is
sufficient. If the results are abnormal in at least two tests, further andrological investigation is
indicated. It is important to differentiate between the following:

oligozoospermia: < 15 million spermatozoa/mL;

asthenozoospermia: < 32% progressive motile spermatozoa;

teratozoospermia: < 4% normal forms.

Often, all three anomalies occur simultaneously, which is defined as
oligo-astheno-teratozoospermia (OAT) syndrome. As in azoospermia, in extreme cases of
oligozoospermia (spermatozoa < 1 million/mL), there is an increased incidence of obstruction of
the male genital tract and genetic abnormalities.

4.2.2.Recommendations for the diagnostic evaluation of male infertility

Recommendations

Strength
rating

Include the fertility
status of the female partner in the diagnosis and management of male sub-fertility because
this might determine the final outcome.

Strong

Perform semen
analyses according to the guidelines of the WHO Laboratory Manual for the Examination and
Processing of Human Semen (5th edn).

Strong

Perform further
andrological assessment when semen analysis is abnormal in at least two tests.

Strong

Adhere to the 2000
WHO Manual for the standardised investigation, diagnosis and management of the infertile
male for diagnosis and evaluation of male sub-fertility.

Surgery that may compromise
vascularisation of the testes and lead to testicular atrophy

Idiopathic

Unknown aetiology

Unknown pathogenesis

5.1.2.Diagnostic evaluation

Routine investigations include semen analysis and hormonal determinations. Other
investigations may be required depending on the individual situation. Typical findings from the history and physical examination of a patient with
testicular deficiency are:

cryptorchidism (uni- or bilateral);

testicular torsion and trauma;

genitourinary infection;

exposure to environmental toxins;

gonadotoxic medication (anabolic drugs, SSRIs, etc);

exposure to radiation or cytotoxic agents;

testicular cancer;

absence of testes;

abnormal secondary sexual characteristics;

gynaecomastia;

abnormal testicular volume and/or consistency;

varicocele.

5.1.2.1.Semen analysis

In non-obstructive azoospermia (NOA), semen analysis shows normal ejaculate volume
and azoospermia after centrifugation. A recommended method is semen centrifugation at 3000 g for
fifteen minutes and a thorough microscopic examination by phase contrast optics at ×200
magnification of the pellet. All samples can be stained and re-examined microscopically [14].

5.1.2.2.Hormonal determinations

In men with testicular deficiency, hypergonadotropic hypogonadism is usually
present, with high levels of follicle-stimulating hormone (FSH) and luteinising hormone (LH), and
with or without low levels of testosterone. Generally, the levels of FSH correlate with the number
of spermatogonia: when spermatogonia are absent or markedly diminished, FSH values are usually
elevated; when the number of spermatogonia is normal, but maturation arrest exists at the
spermatocyte or spermatid level, FSH values are within the normal range. However, for an individual
patient, FSH levels do not accurately predict the spermatogenesis status because men with maturation
arrest histology could have normal FSH and testis volume and still be azoospermic [15,16].

5.1.2.3.Ultrasonography

In addition to physical examination, a scrotal US may be helpful in finding signs
of obstruction (e.g., dilatation of rete testis, enlarged epididymis with cystic lesions, or absent
vas deferens) and may demonstrate signs of testicular dysgenesis (e.g., non-homogeneous testicular
architecture and microcalcifications) and testis tumours. For patients with a low seminal volume and
in whom distal obstruction is suspected, transrectal ultrasound (TRUS) is essential [13].

5.1.2.4.Testicular biopsy

Testicular biopsy can be part of intracytoplasmic sperm injection (ICSI) treatment
in patients with clinical evidence of NOA. Testicular sperm extraction (TESE) is the technique of
choice. Spermatogenesis may be focal, which means that in about 50% of men with NOA, spermatozoa can
be found and used for ICSI. There is a good correlation between the histology found upon diagnostic
biopsy and the likelihood of finding mature sperm cells during testicular sperm retrieval and ICSI [17-19].
However, no threshold value has been found for FSH, inhibin B, or testicular volume and successful
sperm harvesting. When there are complete AZFa and AZFb microdeletions, the likelihood of sperm
retrieval is virtually zero and therefore TESE procedures are contraindicated. Microsurgical TESE
yields the highest sperm retrieval rates, and multiple TESE is superior to conventional TESE.
Microsurgical TESE should be preferred in severe cases of non-obstructive azoospermia [20-24].

The results of ICSI are worse when using sperm retrieved from men with NOA compared
to sperm from ejaculated semen and from men with obstructive azoospermia (OA) [25-29].
Birth rates are lower in NOA vs. OA (19% vs 28%) [30,31].
ICSI results in significantly lower fertilisation and implantation rates. In longitudinal studies
including patients with NOA as defined by testicular histopathology, only one out of seven NOA
patients embarking for TESE and eventually ICSI will father their genetically-own child [32].
Neonatal health in terms of birth parameters, major anomalies and chromosomal aberrations in a large
cohort of children born after use of non-ejaculated sperm are comparable to the outcome of children
born after use of ejaculated sperm [33].

5.1.3.Summary of evidence and recommendations

Summary of evidence

LE

The WHO laboratory manual
proposes reference values based on fertility therefore these reference values do not allow classification of men as infertile.

2a

Impaired spermatogenesis is
often associated with elevated FSH concentration.

3

For patients with NOA who have
spermatozoa in their testicular biopsy, intracytoplasmic sperm injection (ICSI) with fresh or cryopreserved spermatozoa is
the only therapeutic option. Spermatozoa are found by a TESE procedure in about 50% of patients with
NOA.

2a

Pregnancies and live births
are eventually obtained in 30-50% of couples with NOA, when spermatozoa have been found in the testicular biopsy.

3

Recommendations

Strength
rating

For men who are
candidates for sperm retrieval, give appropriate genetic counselling even when testing for
genetic abnormalities was negative.

5.2.Genetic disorders in infertility

All urologists working in andrology must have an understanding of genetic
abnormalities associated with infertility, so that they can provide correct advice to couples
seeking fertility treatment. Men with very low sperm counts can be offered a reasonable chance of
paternity, using in vitro fertilisation (IVF), ICSI and sperm
harvesting from the testes in case of azoospermia. However, the spermatozoa of infertile men show an
increased rate of aneuploidy, structural chromosomal abnormalities, and DNA damage, carrying the
risk of passing genetic abnormalities to the next generation. Current routine clinical practice is
based on the screening of genomic DNA from peripheral blood samples, however, screening of
chromosomal anomalies in spermatozoa is also feasible and can be performed in selected cases [34].

5.2.1.Chromosomal abnormalities

Chromosome abnormalities can be numerical (e.g. trisomy) or structural (e.g.
inversions or translocations). In a survey of pooled data from eleven publications, including 9,766
infertile men, the incidence of chromosomal abnormalities was 5.8% [35].
Of these, sex chromosome abnormalities accounted for 4.2% and autosomal abnormalities for 1.5%. In
comparison, the incidence of abnormalities was 0.38% in pooled data from three series, with a total
of 94,465 newborn male infants, of which 131 (0.14%) were sex chromosome abnormalities and 232
(0.25%) autosomal abnormalities [35].
The frequency of chromosomal abnormalities increases as testicular deficiency becomes more severe.
Patients with a spermatozoa count < 5 million/mL already show a ten-fold higher incidence (4%) of
mainly autosomal structural abnormalities compared with the general population [36,37].
Men with NOA are at highest risk, especially for sex chromosomal anomalies.

Based on the frequencies of chromosomal aberrations in patients with different
sperm concentration, karyotype analysis is indicated in men with azoospermia or oligozoospermia
(spermatozoa < 10 million/mL) [37].
This broad selection criteria implies relatively low specificity. However, it remains a valid
threshold until studies, evaluating the cost-effectiveness, in which costs of adverse events due to
chromosomal abnormalities (e.g. miscarriages and children with congenital anomalies) are included,
will be performed [38].
If there is a family history of recurrent spontaneous abortions, malformations or mental
retardation, karyotype analysis should be requested, regardless of the sperm concentration.

Klinefelter’s syndrome is the most common sex chromosome abnormality [39].
Adult men with Klinefelter’s syndrome have small firm testicles, devoid of germ cells. The phenotype
varies from a normally virilised man to one with the stigmata of androgen deficiency, including
female hair distribution, scant body hair, and long arms and legs due to late epiphyseal closure.
Leydig cell function is commonly impaired in men with Klinefelter’s syndrome [40].
Testosterone levels may be normal or low, oestradiol levels normal or elevated, and FSH levels
increased. Libido is often normal despite low testosterone levels, but androgen replacement may be
needed as the patient ages.

Germ cell presence and sperm production are variable in men with Klinefelter’s
mosaicism, 46,XY/47,XXY. Based on sperm fluorescence in situ
hybridisation (FISH) studies showing an increased frequency of sex chromosomal abnormalities and
increased incidence of autosomal aneuploidy (disomy for chromosomes 13, 18 and 21), concerns have
been raised about the chromosomal normality of the embryos generated through ICSI [41].

The production of 24,XY sperm has been reported in 0.9% and 7.0% of men with
Klinefelter’s mosaicism [42,43]
and in 1.36-25% of men with somatic karyotype 47,XXY [44-47].
In patients with azoospermia, TESE (42%) or micro-TESE (57%) can be proposed as a therapeutic option
since spermatozoa can be recovered in about 50% of cases [48].
There is growing evidence that TESE or micro-TESE yields higher sperm recovery rates when done at a
younger age. Numerous healthy children have been born using ICSI without pre-implantation genetic
diagnosis (PGD) and the conception of one 47,XXY foetus has been reported [39].

Medical follow-up (possibly every year) of men with Klinefelter’s syndrome is
required and androgen replacement therapy should be started after fertility issues have been
addressed and when testosterone level is in the range of hypoandrogenism. Since this syndrome is
associated with a number of general health problems, appropriate medical follow-up is advised [49].

TESE in peri-pubertal or pre-pubertal Klinefelter boys aiming at cryopreservation
of testicular spermatogonial stem cells is to be considered experimental and should only be
performed within a research protocol [50]
and the same applies to sperm retrieval in older boys who have not considered their fertility
potential [51].

5.2.1.2.Autosomal abnormalities

Genetic counselling should be offered to all couples seeking fertility treatment
(including IVF/ICSI) when the male partner has an autosomal karyotype abnormality. The most common
autosomal karyotype abnormalities are Robertsonian translocations, reciprocal translocations,
paracentric inversions, and marker chromosomes. It is important to look for these structural
chromosomal anomalies because there is an increased associated risk of aneuploidy or unbalanced
chromosomal complements in the foetus. As with Klinefelter’s syndrome, sperm FISH analysis provides
a more accurate risk estimation of affected offspring, however, the diffusion of this genetic test
is largely limited by the availability of laboratories able to perform this analysis. When IVF/ICSI
is carried out for men with translocations, PGD or amniocentesis should be performed [52,53].

5.2.1.3.Sperm chromosomal abnormalities

Sperm can be examined for their chromosomal constitution using multicolour FISH
both in men with normal karyotype and with anomalies. Aneuploidy in sperm, particularly sex
chromosome aneuploidy, is associated with severe damage to spermatogenesis [35,54-56]
and with translocations [57].
Florescence in situ hybridisation analysis of spermatozoa is only indicated for specific andrology conditions e.g. macrocephalia [56].

5.2.2.Genetic defects

5.2.2.1.X-linked genetic disorders and male fertility

Each man has only one X-chromosome. An X-linked recessive disorder manifests in
males. The defect will be transmitted to daughters, but not to sons.

5.2.2.2.Kallmann syndrome

Patients with Kallmann syndrome have hypogonadotropic hypogonadism and anosmia, but
may also have other clinical features, including facial asymmetry, cleft palate, colour blindness,
deafness, maldescended testes, and unilateral renal aplasia. This syndrome can be due to mutation in
the Kalig-1 gene (on the X-chromosome) or in several other autosomal genes and should be tested [56,57].

Spermatogenesis can be relatively easily induced by hormonal treatment [58],
therefore, genetic screening prior to therapy is advisable although it is limited by the rarity of
specialised genetic laboratories that can offer this genetic test. Treatment with gonadotropins
allows natural conception in most cases, even for men with a relatively low sperm count. Thus,
identification of the involved gene (X-linked, autosomal dominant or recessive) can help to provide
more accurate genetic counselling, that is, risk estimation for transmission to the offspring.

5.2.2.3.Mild androgen insensitivity syndrome

The Androgen Receptor (AR) gene is located on the long arm of the X-chromosome.
Mutations in the AR gene may result in mild to complete androgen insensitivity. The phenotypic
features of complete androgen insensitivity syndrome are female external genitalia and absence of
pubic hair (Morris syndrome). In partial androgen insensitivity syndrome, phenotypes range from
predominantly female phenotype through ambiguous genitalia, to predominantly male phenotype with
micropenis, perineal hypospadias, and cryptorchidism. The latter phenotype is also termed
Reifenstein syndrome. In the forementioned severe forms of androgen resistance, there is no risk of
transmission because affected men cannot generate their own biological children using the current
technologies. Patients with mild androgen insensitivity syndrome have male infertility as their
primary or even sole symptom. Disorders of the androgen receptor causing infertility in the absence
of any genital abnormality are rare, and only a few mutations have been reported in infertile [59-62]
or fertile [63]
men.

5.2.2.4.Other X-disorders

An unexpectedly high number of genes with a testis-specific or enriched expression
pattern have been identified on the X-chromosome, and in particular, premeiotic genes are
over-represented on the X-chromosome compared with autosomal chromosomes [64].
Nevertheless, to date only a few genes have been screened in relatively small populations and none of them appear relevant for male infertility [65,66]. On
the other hand, two recent independent studies showed a significantly higher deletion load on the
X-chromosome in men with spermatogenic failure with respect to normozoospermic controls [67,68].

5.2.3.Y-chromosome and male infertility

Microdeletions on the Y-chromosome are termed AZFa, AZFb and AZFc [69].
Clinically relevant deletions remove partially, or in most cases completely, one or more of the AZF
regions, and are the most frequent molecular genetic cause of severe oligozoospermia and azoospermia
[70].
In each AZF region, there are several spermatogenesis candidate genes [71].
Deletions occur en bloc (i.e. removing more than one gene),
thus, it is not possible to determine the role of a single AZF gene from the AZF deletion phenotype
and it is unclear if they all participate in spermatogenesis. Gene-specific deletions, which remove
a single gene, have been reported only in the AZFa region and concern the USP9Y gene. These studies
have suggested that USP9Y is most likely to be a “fine tuner” of sperm production, and its specific
screening is not advised [72].

5.2.3.1.Clinical implications of Y
microdeletions

The clinical significance of Yq microdeletions can be summarised as follows:

They are not found in normozoospermic men, proving there is a clear cut cause-and-effect
relationship between Y-deletions and spermatogenic failure [73].

The highest frequency of Y-deletions is found in azoospermic men (8-12%), followed by
oligozoospermic (3-7%) men.

AZFc deletions are most common (65-70%), followed by Y-deletions of the AZFb and AZFb+c or
AZFa+b+c regions (25-30%). AZFa region deletions are rare (5%).

Complete removal of the AZFa region is associated with severe testicular phenotype (Sertoli cell
only syndrome), while complete removal of the AZFb region is associated with spermatogenic rest.
Complete removal of the AZFc region causes a variable phenotype ranging from azoospermia to
oligozoospermia.

Classical (complete) AZF deletions do not confer a risk for cryptorchidism or testicular cancer
[74].

The specificity and genotype/phenotype correlation reported above means that
Y-deletion analysis has both a diagnostic and prognostic value for testicular sperm retrieval [74].

5.2.3.1.1.Testing for Y microdeletions

Indications for AZF deletion screening are based on sperm count and include
azoospermia and severe oligozoospermia (spermatozoa count < 5 million/mL). Thanks to the European
Academy of Andrology (EAA) guidelines and the European Molecular Genetics Quality Network external
quality control programme (http://www.emqn.org/emqn/),
Yq testing has become more reliable in different routine genetic laboratories. The EAA guidelines
provide a set of primers capable of detecting > 95% of clinically relevant deletions [75].

5.2.3.1.2.Genetic counselling for AZF
deletions

After conception, any Y-deletions are transmitted obligatorily to the male
offspring, and genetic counselling is therefore mandatory. In most cases, father and son have the
same microdeletion [75],
but occasionally the son has a larger one [76].
The extent of spermatogenic failure (still in the range of azoo-/oligozoospermia) cannot be
predicted entirely in the son, due to the different genetic background and the presence or absence
of environmental factors with potential toxicity for reproductive function. A significant proportion
of spermatozoa from men with complete AZFc deletion are nullisomic for sex chromosomes [77,78],
indicating a potential risk for any offspring to develop 45,X0 Turner’s syndrome and other
phenotypic anomalies associated with sex chromosome mosaicism, including ambiguous genitalia [79].
Despite this theoretical risk, babies born from fathers affected by Yq microdeletions are
phenotypically normal [74,75].
This could be due to the reduced implantation rate and a likely higher risk of spontaneous abortion
of embryos bearing a 45,X0 karyotype. When ICSI is used in the presence of a Y microdeletion,
long-term follow-up of any male children is needed with respect to their fertility status, and
cryopreservation of spermatozoa at a young age can be considered.

5.2.3.1.3.Y-chromosome: ‘gr/gr’ deletion

A new type of Yq deletion, known as the gr/gr deletion, has been described in the
AZFc region [80].
This deletion removes half of the gene content of the AZFc region, affecting the dosage of multicopy
genes mapping inside this region. This type of deletion confers a 2.5-8 fold increased risk for
oligozoospermia [75,81-83].
The frequency of gr/gr deletion in oligozoospermic patients is ~4%.

According to four meta-analyses, gr/gr deletion is a significant risk factor for
impaired sperm production [82,83].
It is worth noting that both the frequency of gr/gr deletion and its phenotypic expression vary
between different ethnic groups, depending on the Y-chromosome background. For example, in some Y
haplogroups, the deletion is fixed and appears to have no negative effect on spermatogenesis.
Consequently, the routine screening for gr/gr deletion is still a debated issue, especially in those
laboratories serving diverse ethnic and geographic populations. A large multicentre study has shown
that gr/gr deletion is a potential risk factor for testicular germ cell tumours [84].
However, these data need further confirmation in an ethnically and geographically matched
case-control study setting. For genetic counselling it is worth noting that partial AZFc deletions,
gr/gr and b2/b3, may predispose to complete AZFc deletion in the next generation [85,86].

Several inherited disorders are associated with severe or considerable generalised
abnormalities and infertility. Among them, Prader-Willy Syndrome, Bardet-Biedl Syndrome, Noonan’s
Syndrome, Myotonic dystrophy, dominant polycystic kidney disease, 5 α-reductase
deficiency, etc. Patients with these defects will be well known to doctors, often from childhood. A
fertility problem must be managed in the context of the care of the man as a whole including the
couple’s ability to care for a child.

5.2.4.Cystic fibrosis mutations and male infertility

Cystic fibrosis (CF) is a fatal autosomal-recessive disorder. It is the most common
genetic disease of Caucasians; 4% are carriers of gene mutations involving the CF transmembrane
conductance regulator (CFTR) gene located on chromosome 7p. It encodes a membrane protein that
functions as an ion channel and influences the formation of the ejaculatory duct, seminal vesicle,
vas deferens and distal two-thirds of the epididymis.

Congenital bilateral absence of the vas deferens (CBAVD) is associated with CFTR
gene mutations and was found in ~2% of men with OA attending a clinic in Edinburgh, UK [87].
The incidence in men with OA varies between different countries. The clinical diagnosis of absent
vasa is easy to miss and all men with azoospermia should be very carefully examined to exclude
CBAVD, particularly those with a semen volume < 1.5 mL and pH < 7.0. Approximately 1,500
mutations are listed on the CFTR database http://www.genetsickkids.on.ca/cftr/.
The most frequently found mutations are the F508, R117H and W1282X, but their frequency and the
presence of other mutations largely depend on the ethnicity of the patient [88,89].
Given the functional relevance of a DNA variant (the 5T allele) in a non-coding region of CFTR [84],
it is now considered a mild CFTR mutation rather than a polymorphism and it should be analysed in
each CBAVD patient. As more mutations are defined and tested for, almost all men with CBAVD will
probably be found to have mutations. It is not practical to test for all known mutations, because
many have a very low prevalence in a particular population. Routine testing is usually restricted to
the most common mutations in a particular community through the analysis of a mutation panel. Given
that this is a recessive disease if a second mutation is not found with the routine panel, a second
step analysis is advised which comprises the direct sequencing of the entire gene. Men with CBAVD
often have mild clinical stigmata of CF (e.g., history of chest infections). When a man has CBAVD,
it is important to test also his partner for CF mutations. If the female partner is found to be a
carrier of CFTR mutations, the couple must consider very carefully whether to proceed with ICSI
using the male’s sperm, as the risk of having a child with CF or CBAVD will be 50%, depending on the
type of mutations carried by the parents. If the female partner is negative for known mutations, the
risk of being a carrier of unknown mutations is ~0.4% [90].

5.2.4.1.Unilateral or bilateral
absence/abnormality of the vas and renal anomalies

Unilateral absence of the vas deferens is usually associated with ipsilateral
absence of the kidney and probably has a different genetic causation [91].
Consequently, in these subjects CFTR mutation screening is not indicated. Men with unilateral
absence of the vas deferens are usually fertile, and the condition is most commonly encountered as
an incidental finding in the vasectomy clinic. CFTR gene mutation screening is indicated in men with
unilateral absence of the vas deferens with normal kidneys. An abdominal US should be undertaken
both in unilateral and bilateral absence of vas deferens. Findings may range from unilateral absence
of the vas deferens with ipsilateral absence of the kidney, to bilateral vessel and renal
abnormalities, such as pelvic kidney [92].

5.2.4.2.Unknown genetic disorders

Considering the predicted high number of genes involved in male gametogenesis, it
is likely that most idiopathic forms of spermatogenic disturbances are caused by mutations or
polymorphisms in spermatogenesis candidate genes [65].
However, despite an intensive search for new genetic factors, no clinically relevant gene mutations
or polymorphisms (except those related to the Y-chromosome) have so far been identified [65,90,93].
The introduction of new analytical approaches has provided evidence for the importance of Copy
Number Variations (CNVs) [67,68]
and further advances are expected with Next Generation Sequencing. Intracytoplasmic sperm injection
is used to enable men with severely damaged spermatogenesis to father children in situations
formerly considered hopeless and where very few spermatozoa can be obtained. This has led to concern
that children may be born with a foetal abnormality, because ICSI may enable defective sperm to
bypass the selective processes of the female genital tract and egg covering. Intracytoplasmic sperm
injection babies have a higher risk of de novo sex chromosomal
aberrations (about a threefold increase compared with natural conceptions) and paternally inherited
structural abnormalities. Treatment with assisted reproductive technology was associated with
increased risk of cardiovascular, musculoskeletal, urogenital, and gastrointestinal defects and
cerebral palsy [94-96].

5.2.4.3.DNA fragmentation in spermatozoa

There is increased DNA damage in spermatozoa from men with oligozoospermia. This
increase is associated with reduced chances of natural conception and an increased chance of early
pregnancy loss [97].

5.2.4.4.Genetic counselling and ICSI

Initially, the couple should be given full information about the risks to the child
in order to help them decide whether to proceed with ICSI. Where there is conflict between the
wishes of the couple and the interests of the future child, it may be ethically correct to withhold
therapy. When both partners are known to carry defects (e.g., CFTR mutations), there is up to a 50%
chance of the child developing a clinical condition. Many clinicians and infertility clinic
personnel may consider it unethical to proceed because their duty of care to the future child and
the interests of society outweigh the wishes of the individual couple. If there is a conflict that
cannot be resolved by agreement, the interests of a future child probably take precedence over the
interests of a couple. The couple also needs to give consideration to pre-implantation
diagnosis.

5.2.5.Summary of evidence and recommendations for genetic disorders in male infertility

Summary of evidence

LE

In men with spermatogenic
damage there is a higher prevalence of chromosome abnormalities, reaching the highest frequency in NOA men.

1b

AZF deletions are clear-cut
causes of spermatogenic impairments with diagnostic and prognostic value for TESE.

1a

AZF deletions will be
transmitted to the son.

1a

gr/gr deletion has been
confirmed as a significant risk factor for impaired sperm production, whereas further evidence of the prognostic significance of gr/gr and
development of a testicular germ cell tumour is needed.

Provide genetic
counselling in all couples with a genetic abnormality found on clinical or genetic
investigation and in patients who carry a (potential) inheritable disease.

Strong

For all men with
Klinefelter’s syndrome, provide long-term endocrine follow-up and appropriate medical
treatment, if necessary.

Strong

Do not test for
microdeletions in men with obstructive azoospermia (OA) since spermatogenesis should be
normal.

Strong

Inform men with Yq
microdeletion and their partners who wish to proceed with intracytoplasmic sperm injection
(ICSI) that microdeletions will be passed to sons, but not to daughters.

Strong

In men with
structural abnormalities of the vas deferens (unilateral or bilateral absence with no renal
agenesis), test the man and his partner for cystic fibrosis transmembrane conductance
regulator gene mutations.

Strong

5.3.Obstructive azoospermia

Obstructive azoospermia is the absence of spermatozoa and spermatogenetic cells in
semen and post-ejaculate urine due to obstruction. OA is less common than NOA and occurs in 15-20%
of men with azoospermia. Men with OA present with normal FSH, normal size testes, and epididymal
enlargement. Sometimes, the vas deferens is absent (CBAVD or Congenital Unilateral Absence of the
Vas Deferens (CUAVD)). Obstruction in primary infertile men is frequently present at the epididymal
level.

5.3.1.Classification

5.3.1.1.Intratesticular obstruction

Intratesticular obstruction occurs in 15% of men with OA [98].
Congenital forms are less common than acquired forms (post-inflammatory or post-traumatic).

5.3.1.2.Epididymal obstruction

Epididymal obstruction is the most common cause of OA, affecting 30-67% of
azoospermic men [98-102].
Congenital epididymal obstruction usually manifests as CBAVD, which is associated with at least one
mutation of the CF gene in 82% of cases [101].
Congenital forms of epididymal obstruction include chronic sinopulmonary infections (Young’s
syndrome) [103].
Acquired forms secondary to acute (e.g., gonococcal) and subclinical (e.g., chlamydial) epididymitis
are most common [104,105].
Other causes may be trauma or surgical intervention [106,107].

5.3.1.3.Vas deferens obstruction

Vas deferens obstruction is the most common cause of acquired obstruction following
vasectomy [104].
Approximately 2-6% of these men request vasectomy reversal (see Chapter 5.6). Vasal obstruction may
also occur after hernia repair [108,109].
The most common congenital vasal obstruction is CBAVD, often accompanied by CF. Unilateral agenesis
or a partial defect is associated with contralateral seminal duct anomalies or renal agenesis in 80%
and 26% of cases, respectively [110]
(see Chapter 5.2).

5.3.1.4.Ejaculatory duct
obstruction

Ejaculatory duct obstruction is found in 1-3% of cases of OA [98]
and is classified as either cystic or post-inflammatory. Cystic obstructions are usually congenital
(i.e., Mullerian duct cyst or urogenital sinus/ejaculatory duct cysts) and are typically midline. In
urogenital sinus abnormalities, one or both ejaculatory ducts empty into the cyst [111],
while in Mullerian duct anomalies, the ejaculatory ducts are laterally displaced and compressed by
the cyst [112].
Paramedian or lateral intraprostatic cysts are rare [113].
Post-inflammatory obstructions of the ejaculatory duct are usually secondary to urethroprostatitis [114].
Congenital or acquired complete obstructions of the ejaculatory ducts are commonly associated with
low semen volume, decreased or absent seminal fructose, and acid pH. The seminal vesicles are
usually dilated (anterior-posterior diameter > 15 mm) [114,115].

5.3.1.5.Functional obstruction of the distal
seminal ducts

Functional obstruction of the distal seminal ducts might be attributed to local
neuropathy [116].
This abnormality is often associated with urodynamic dysfunction. Impaired sperm transport may be
idiopathic or associated with selective serotonin re-uptake inhibitor (SSRI) medication as well.

5.3.2.Diagnostic evaluation

5.3.2.1.Clinical history

Clinical history taking should follow the investigation and diagnostic evaluation
of infertile men (See Chapter 4.2).

5.3.2.2.Clinical
examination

Clinical examination should follow suggestions for the diagnostic evaluation of
infertile men. OA is indicated by at least one testis with a volume > 15 mL, although a smaller volume may be
found in some patients with:

OA and concomitant partial testicular failure;

enlarged and dilated epididymis;

nodules in the epididymis or vas deferens;

absence or partial atresia of the vas.

5.3.2.3.Semen analysis

At least two examinations must be carried out at an interval of two to three
months, according to the WHO (see Chapter 4.2). Azoospermia means the inability to detect
spermatozoa after centrifugation at ×400 magnification. When semen volume is low, a search must be
made for spermatozoa in urine after ejaculation. Absence of spermatozoa and immature germ cells in
semen smears suggest complete seminal duct obstruction.

5.3.2.4.Hormone levels

Serum FSH levels should be normal, but do not exclude a testicular cause of
azoospermia. FSH level is normal in 40% of men with primary spermatogenic failure. Inhibin B seems
to have a higher predictive value for normal spermatogenesis [102].

5.3.2.5.Testicular biopsy

In selected cases, testicular biopsy is indicated to exclude spermatogenic failure.
Testicular biopsy should be combined with extraction of testicular spermatozoa (i.e., TESE) for
cryopreservation.

5.3.3.Disease management

5.3.3.1.Intratesticular obstruction

Only TESE allows sperm retrieval in these patients and is therefore
recommended.

5.3.3.2.Epididymal obstruction

Microsurgical epididymal sperm aspiration (MESA) [117]
is indicated in men with CBAVD. TESE and PESA (limited cryopreservation) are also viable options [118].
Usually, one MESA procedure provides sufficient material for several ICSI cycles [119]
and it produces high pregnancy and fertilisation rates [120].
In patients with azoospermia due to acquired epididymal obstruction, microsurgical reconstruction is
recommended in couples with a female partner with good ovarian reserve, with the preferred technique
being microsurgical intussusception tubulovasostomy [121].
Anatomical recanalisation following surgery may require three to eighteen months. Before
microsurgery, and in all cases where recanalisation is impossible, epididymal spermatozoa should be
aspirated and cryopreserved for use in ICSI [114].
Patency rates range between 60% and 87% [107,122]
and cumulative pregnancy rates between 10% and 43%. Recanalisation success rates may be adversely
affected by pre-operative and intra-operative findings.

5.3.3.3.Proximal vas deferens obstruction

Proximal vas deferens obstruction after vasectomy requires microsurgical vasectomy
reversal. Vasovasostomy is also required in rare cases of proximal vasal obstructions. The absence
of spermatozoa in the intra-operative vas deferens fluid suggests the presence of a secondary
epididymal obstruction, especially if the seminal fluid of the proximal vas has a thick “toothpaste”
appearance. Microsurgical tubulovasostomy is then indicated.

5.3.3.4.Distal vas deferens obstruction

It is usually impossible to correct large bilateral vas deferens defects, resulting
from involuntary excision of the vasa deferentia during hernia surgery in early childhood or
previous orchidopexy. In these cases TESE/MESA or proximal vas deferens sperm aspiration [123]
can be used for cryopreservation for future ICSI.

5.3.3.5.Ejaculatory
duct obstruction

The treatment of ejaculatory duct obstruction depends on its aetiology.
Transurethral resection of the ejaculatory ducts (TURED) [114]
can be used in large post-inflammatory obstruction and when one or both ejaculatory ducts empty into
an intraprostatic midline cyst. Resection may remove part of the verumontanum. In cases of
obstruction due to a midline intraprostatic cyst, incision or unroofing of the cyst is required [114].
Intra-operative TRUS makes this procedure safer. If distal seminal tract evaluation is carried out
at the time of the procedure, installation of methylene blue dye into the vas deferens can help to
document opening of the ducts. The limited success rate of surgical treatment of ejaculatory duct
obstruction in terms of spontaneous pregnancies should be weighed against sperm aspiration and ICSI.
Complications following TURED include retrograde ejaculation due to bladder neck injury and urine
reflux into the ejaculatory ducts, seminal vesicles, and vasa. The alternatives to TURED are MESA,
TESE, proximal vas deferens sperm aspiration, seminal vesicle ultrasonically guided aspiration, and
direct cyst aspiration. Spermatozoa can then be retrieved by antegrade seminal tract washout [124].

5.3.4.Summary of evidence and recommendations for obstructive azoospermia

Summary of evidence

LE

Obstructive lesions of the
seminal tract are frequent in azoospermic or severely oligozoospermic patients with normal-sized testes and normal reproductive
hormones.

3

Recommendations

Strength
rating

Perform microsurgical
vasovasostomy or tubulovasostomy for azoospermia caused by vasal or epididymal
obstruction.

Strong

Use sperm retrieval
techniques, such as microsurgical epididymal sperm aspiration, testicular sperm extraction
and percutaneous epididymal sperm aspiration only when facilities for cryostorage are
available.

Strong

5.4.Varicocele

Varicocele is a common genital abnormality which may be associated with the
following andrological conditions:

failure of ipsilateral testicular growth and development;

symptoms of pain and discomfort;

male subfertility;

hypogonadism.

5.4.1.Classification

The following classification of varicocele [125]
is useful in clinical practice:

Subclinical: not palpable or visible at rest or during Valsava manoeuvre, but can be shown by
special tests (Doppler ultrasound studies).

Grade 1: palpable during Valsava manoeuvre, but not otherwise.

Grade 2: palpable at rest, but not visible.

Grade 3: visible and palpable at rest.

5.4.2.Diagnostic evaluation

The diagnosis of varicocele is made by clinical examination and should be confirmed
by US investigation and colour Duplex analysis [125].
In centres where treatment is carried out by antegrade or retrograde sclerotherapy or embolisation,
diagnosis is additionally confirmed by X-ray..

5.4.3.Basic considerations

5.4.3.1.Varicocele and fertility

Varicocele is a physical abnormality present in 11.7% of adult men and in 25.4% of
men with abnormal semen analysis [126].
The exact association between reduced male fertility and varicocele is unknown, but a recent
meta-analysis showed that semen improvement is usually observed after surgical correction [127].
Varicocelectomy can reverse sperm DNA damage [128].

5.4.3.2.Varicocelectomy

Varicocele repair has been a subject of debate for several decades. A meta-analysis
of RCTs and observational studies in men with only clinical varicoceles showed that surgical
varicocelectomy significantly improves semen parameters in men with abnormal semen parameters
including men with non-obstructive azoospermia [127,129,130].

In RCTs varicocele repair in men with a subclinical varicocele was found to be
ineffective in increasing the chance of spontaneous pregnancies [131].
Also, in randomised studies that included mainly men with normal semen parameters no benefit was
found in favour of treatment over observation. A Cochrane review from 2013 concluded that there is
evidence to suggest that treatment of a varicocele in men from couples with otherwise unexplained
sub-fertility may improve a couple’s chance for spontaneous pregnancies [132].
In a subgroup analyses of five RCTs comparing treatment to observation in men with a clinical
varicocele, oligozoospermia and otherwise unexplained infertility, the analyses favoured treatment,
with a combined odds ratio (OR) of 2.39 (95% CI 1.56 to 3.66) [132].
A recent meta-analysis has reported that varicocelectomy may improve outcomes following insert
assisted reproductive techniques (ART) in oligozoospermic men [133].

5.4.3.3.Prophylactic Varicocelectomy

In adolescents with a varicocele, there is a significant risk of over-treatment
since most adolescents with a varicocele will have no problem achieving pregnancy later in life [134].
Prophylactic treatment is only advised in case of documented growth deterioration of the testis as
documented by serial clinical examinations and impaired semen quality.

5.4.4.Disease management

Several treatments are available for varicoceles (Table 4). Current evidence
indicates that microsurgical varicocelectomy is the most effective method among the different
varicocelectomy techniques [134].
Microsurgical repair results in fewer complications and lower recurrence rates compared to the other
techniques. This procedure, however, requires microsurgical training. The various other techniques
are still considered viable options, although recurrences and hydrocele formation are more likely to
occur.

5.4.5.Summary of evidence and recommendations for varicocele

Summary of evidence

LE

The presence of varicocele in
some men is associated with progressive testicular damage from adolescence onwards and a consequent reduction in
fertility.

2a

Although the treatment of
varicocele in adolescents may be effective, there is a significant risk of over-treatment:
the majority of boys with a varicocele will have no fertility problems later in life.

3

Varicocele repair was shown to
be effective in men with oligospermia, a clinical varicocele and otherwise unexplained infertility.

1a

Recommendations

Strength
rating

Treat varicoceles in
adolescents with ipsilateral reduction in testicular volume and evidence of progressive
testicular dysfunction.

Weak

Do not treat
varicoceles in infertile men who have normal semen analysis and in men with a subclinical
varicocele.

Strong

Treat men with a
clinical varicocele, oligozoospermia and otherwise unexplained infertility in the
couple.

Weak

5.5.Hypogonadism

Hypogonadism is characterised by impaired testicular function, which may affect
spermatogenesis and/or testosterone synthesis. The symptoms of hypogonadism depend on the degree of
androgen deficiency and if the condition develops before or after pubertal development of the
secondary sex characteristics.

5.5.1.Epidemiology and aetiology

The aetiological and pathogenetic mechanisms of male hypogonadism can be divided
into three main categories:

Idiopathic hypogonadotropic hypogonadism is characterised by low levels of
gonadotropins and sex steroid in the absence of anatomical or functional abnormalities of the
hypothalamic-pituitary-gonadal axis [145].
Idiopathic hypogonadotropic hypogonadism may be an isolated condition or may be associated with
anosmia/hyposmia (Kallmann syndrome). Genetic factors causing a deficit of gonadotropins may act at
the hypothalamic or pituitary level. Mutations in candidate genes (X-linked or autosomal) can be
found in ~30% of congenital cases [145]
and should be screened for prior to assisted reproduction [146].
Acquired hypogonadotropic hypogonadism can be caused by some drugs, hormones, anabolic steroids, or
tumours.

A suspected tumour requires imaging [computed tomography (CT) or magnetic resonance
imaging (MRI)] of the sella region and a complete endocrine work-up. Normal androgen levels and
subsequent development of secondary sex characteristics (in cases of onset of hypogonadism before
puberty) and a eugonadal state can be achieved by androgen replacement alone. However, stimulation
of sperm production requires treatment with human chorionic gonadotropin (hCG) combined with
recombinant FSH, urinary highly purified FSH or human menopausal gonadotropins (HMGs) [147,148].
If hypogonadotropic hypogonadism is hypothalamic in origin, an alternative to hCG treatment is
pulsatile GnRH [149].
In patients who have developed hypogonadism before puberty and have not been treated with
gonadotropins or GnRH, one to two years of therapy may be needed to achieve sperm production.

Many conditions in men with testicular failure are associated with
hypergonadotropic hypogonadism (Table 5, see also Chapter 5.2). Most conditions listed in Table 5
only affect the reproductive function of the testes so that only the FSH level is elevated. However,
it has been reported that men with infertility are at higher risk for developing impaired Leydig
cell function [150],
while men with Klinefelter’s syndrome often show high LH values and develop hypoandrogenism with
ageing [151].
A decrease in testosterone blood concentrations after extensive testicular biopsy in the context of
TESE/ICSI has been observed, raising questions about the need for long-term endocrine follow-up of
these patients [152].
Laboratory diagnosis of hypergonadotropic hypogonadism is based on a high level of FSH, decreased
serum testosterone, and increased LH levels [146].
Testosterone levels should be evaluated in view of the serum concentration of sex hormone binding
globulin (SHBG). Based on levels of total testosterone, albumin and SHBG, free and bioavailable
testosterone can be calculated. Due to diurnal variation, blood samples for testosterone assessment
should be taken before 10.00 am.

Generally, androgen replacement should not be given to men who are considering
parenthood or in case of male infertility. Testosterone suppresses pituitary production of LH and
FSH, therefore, replacement therapy should not be given for infertility. In obese men, low levels of
testosterone may exist due to the conversion of testosterone to oestradiol by the enzyme aromatase [153].
Anti-oestrogens and aromatase inhibitors may help in these patients elevating FSH and LH and
potentially increase sperm quality, next to weight reduction. See also EAU Guidelines on Male
Hypogonadism [154].

5.5.4.Recommendations for hypogonadism

Recommendations

Strength
rating

Provide testosterone
replacement therapy for symptomatic patients with primary and secondary hypogonadism who are
not considering parenthood.

Do not use
testosterone replacement for the treatment of male infertility.

Strong

5.6.Cryptorchidism

Cryptorchidism is the most common congenital abnormality of the male genitalia; at
one year of age nearly 1% of all full-term male infants have cryptorchidism [155].
Approximately 30% of undescended testes are non-palpable and may be located within the abdominal
cavity. This guideline only deals with the management in adults.

5.6.1.Aetiology and pathophysiology

It has been postulated that cryptorchidism may be a part of the so-called
testicular dysgenesis syndrome (TDS), which is a developmental disorder of the gonads caused by
environmental and/or genetic influences early in pregnancy. Besides cryptorchidism, TDS includes
hypospadias, reduced fertility, increased risk of malignancy, and Leydig cell dysfunction [156].

5.6.1.1.Pathophysiological effects in
maldescended testes

5.6.1.1.1.Degeneration of
germ cells

The degeneration of germ cells in maldescended testes is apparent after the first
year of life and varies, depending on the position of the testis [157].
During the second year, the number of germ cells declines. Early treatment is therefore recommended
(after the age of six months surgery should be performed within the subsequent year with age
eighteen months the latest) to conserve spermatogenesis and hormone production, as well as to
decrease the risk for tumours [158].
Surgical treatment is the most effective. Medical treatment with GnRH may be beneficial but
long-term follow-up data are required. It has been reported that hCG treatment may be harmful to
future spermatogenesis therefore, the Nordic Consensus Statement on treatment of undescended testes
does not recommend it on a routine basis [159].
See also EAU Guidelines on Paediatric Urology [160].

5.6.1.1.2.Relationship with fertility

Semen parameters are often impaired in men with a history of cryptorchidism [161].
Early surgical treatment may have a positive effect on subsequent fertility [162].
In men with a history of unilateral cryptorchidism, paternity is almost equal (89.7%) to that in men
without cryptorchidism (93.7%). In men with bilateral cryptorchidism, oligozoospermia can be found
in 31% and azoospermia in 42%. In cases of bilateral cryptorchidism, the rate of paternity is only
35-53% [163].

5.6.1.1.3.Germ cell tumours

As a component of the TDS cryptorchidism is a risk factor for testicular cancer and
is associated with testicular microcalcification and intratubular germ cell neoplasia of
unclassified type (ITGCNU); formerly carcinoma in situ (CIS) of
the testes. In 5-10% of testicular cancers, there is a history of cryptorchidism [164].
The risk of a germ cell tumour is 3.6-7.4 times higher than in the general population and 2-6% of
men with a history of cryptorchidism will develop a testicular tumour [155].
Orchidopexy performed before the age of puberty has been reported to decrease the risk of testicular
cancer [165].

5.6.2.Disease management

5.6.2.1.Hormonal treatment

Human chorionic gonadotropin or GnRH is not recommended for the treatment of
cryptorchidism in adulthood.

5.6.2.2.Surgical
treatment

In adolescence removal of intra-abdominal testis (with a normal contralateral
testis) can be recommended, because of the theoretical risk of later malignancy [166].
In adulthood, a palpable undescended testis should not be removed because it still produces
testosterone. Furthermore, as indicated above, correction of bilateral cryptorchidism, even in
adulthood, can lead to sperm production in previously azoospermic men [163].
Vascular damage is the most severe complication of orchidopexy and can cause testicular atrophy in
1-2% of cases. In men with non-palpable testes, the post-operative atrophy rate was 12% in those
cases with long vascular pedicles that enabled scrotal positioning. Post-operative atrophy in staged
orchidopexy has been reported in up to 40% of patients [167].
At the time of orchidopexy, performed in adulthood, testicular biopsy for detection of ITGCNU is
recommended. At the time of orchiectomy in the treatment of germ cell tumours biopsy of the
contralateral testis should be offered to patients at high risk for ITGCNU (i.e. history of
cryptorchidism, < 12 mL. testicular volume, poor spermatogenesis [168]).

5.6.3.Summary of evidence recommendations for cryptorchidism

Summary of evidence

LE

Cryptorchidism is
multifactorial in origin and can be caused by genetic factors and endocrine disruption early in pregnancy.

2a

Cryptorchidism is often
associated with testicular dysgenesis and is a risk factor for infertility and germ cell tumours.

2b

Paternity in men with
unilateral cryptorchidism is almost equal to that in men without cryptorchidism.

5.7.Idiopathic male infertility

No demonstrable cause of infertility is found in at least 44% of infertile men [169].

5.7.1.Disease management

5.7.1.1.Empirical treatments

Lifestyle modification should be considered in patients with idiopathic male
infertility [170,171].
A wide variety of empirical drug treatments of idiopathic male infertility have been used, however,
there is little scientific evidence for an empirical approach [170].
Clomiphene citrate and tamoxifen have been widely used in idiopathic OAT: a meta-analysis reported
some improvement in sperm quality and spontaneous pregnancy rates [172].
Androgens, bromocriptine, α-blockers, systemic corticosteroids and
magnesium supplementation are not effective in the treatment of OAT syndrome. Although
gonadotrophins (HMG/rFSH/hpFSH) might be beneficial in regards to pregnancy rates and live birth in
idiopathic male factor sub-fertility, however, their use should be cautious given the high risk of
bias and heterogeneity of available studies [173].
Men taking oral antioxidants had an associated significant increase in sperm parameters [174]
and in live birth rates in IVF patients in a Cochrane analysis [175].
Concerning natural conception the role of antioxidants needs further investigations [176].

5.7.2.Recommendation for idiopathic male infertility

Recommendations

Strength
rating

Provide medical
treatment for male infertility in patients with of hypogonadotropic hypogonadism.

Strong

No clear
recommendation can be made for treatment of patients with idiopathic infertility using
gonadotropins, anti-oestrogens, and antioxidants.

Strong

5.8.Male contraception

Development of male contraceptive methods is important because up to 40% of women
have an unmet need for family planning, with approximately 80 million women every year having
unintended or unwanted pregnancies [177].
Three of the four methods of male contraception have been in use for hundreds of years (i.e.,
condoms, periodic abstinence, and withdrawal). The typical first-year failure rates of traditional
male methods are high (withdrawal 19%, periodic abstinence 20%, and condoms 3-14%) compared to the
failure rates of 0.1-3% for modern reversible female methods [178].
For men, male contraceptive methods must be acceptable, cheap, reversible, and effective. The method
nearest to being generally available clinically is hormonal male contraception, which is based on
the suppression of gonadotropins and testosterone substitution to maintain male sexual function and
bone mineralisation, and to prevent muscle wasting [179].
Various contraceptive regimens have been developed and tested, including testosterone monotherapy,
androgen/progestin combinations, testosterone with GnRH analogues, and selective androgen and
progestin-receptor modulators [180].
There are racial differences in the response to androgens alone. However, a combination of
testosterone with progestin results in complete suppression of spermatogenesis in all races, and
provides contraceptive efficacy equivalent to female hormonal methods [181].

5.8.1.Vasectomy

Vasectomy is an effective method of permanent male surgical sterilisation [189].
Extensive guidelines on vasectomy were published by the EAU in 2012 [2].
Before vasectomy, the couple should be fully informed about the benefits and risks, especially as an
Australian telephone survey found that 9.2% of respondents regretted having a vasectomy [182].

5.8.1.1.Surgical techniques

Various techniques are available for vasectomy. The least invasive approach is
no-scalpel vasectomy which is also associated with a low rate of complications [183,184].
The most effective occlusion technique is cauterisation of the lumen of the vas deferens and fascial
interposition [185-187].
Most techniques can be carried out safely under local anaesthesia in an outpatient clinic.

5.8.1.1.1.Complications

Vasectomy does not significantly alter spermatogenesis and Leydig cell function.
The volume of ejaculate remains unchanged. Potential systemic effects of vasectomy, including
atherosclerosis, have not been proven, and there is no evidence of a significant increase in any
systemic disease after vasectomy. An increased rate of prostate cancer in men who underwent
vasectomy has not been detected [188,189].
Acute local complications associated with vasectomy include haematoma, wound infection, and
epididymitis in up to 5% of cases [189].
The potential long-term complications (e.g., chronic testicular pain) [190]
must be discussed with the patient before the procedure.

5.8.1.1.2.Vasectomy failure

If an effective occlusion technique is used, the risk of recanalisation after
vasectomy should be < 1% [191].
However, patients should be informed pre-operatively that, although rare, long-term recanalisation
might occur [192].
No motile spermatozoa should be detected three months after vasectomy. Persistent motility is a sign
of vasectomy failure, and the procedure will need to be repeated. A “special clearance” given by the
urologist with non-motile spermatozoa < 100,000/mL is still under discussion [193].

5.8.2.Counselling

Counselling with regard to vasectomy must address the following aspects:

Vasectomy should be considered irreversible.

Vasectomy is associated with a low complication rate; however, because it is an elective
operation, even small risks must be explained, because men (and their partners) might wish to
consider these before giving consent.

Vasectomy can fail, although the failure rate is low.

Couples should be advised to continue with other effective contraception until clearance is
confirmed.

All available data indicate that vasectomy is not associated with any serious, long-term,
side-effects [194].

Vasectomy involving cauterisation and fascial interposition appears to be the most effective
technique in the prevention of early recanalisation [185,191,195].

5.8.3.Vasectomy reversal

A wide range of surgical success rates have been published for vasectomy reversal
(up to 90%), depending on the time between vasectomy and re-fertilisation, type of vasectomy (e.g.,
open-ended or sealed), type of reversal (vasovasostomy or vasoepididymostomy), and whether reversal
was unilateral or bilateral. Microsurgical techniques should be used [196].

5.8.3.1.Length of time since vasectomy

Vasovasostomy results have shown patency rates up to 90%. The longer the interval
is from vasectomy to reversal, the lower the pregnancy rate is. In a study of 1,469 men who had
undergone microsurgical vasectomy reversal, patency and pregnancy rates were 97% and 76%,
respectively, for an interval up to three years after vasectomy; 88% and 53% for three to eight
years, 79% and 44% for nine to fourteen years, and 71% and 30% for > fifteen years [197].

5.8.3.2.Tubulovasostomy

The chance of secondary epididymal obstruction after vasectomy increases with time.
After an interval of ten years, 25% of men appear to have epididymal blockage. If secondary
epididymal obstruction occurs, tubulovasostomy is needed to reverse the vasectomy (see Chapter 5.3)
[198].

According to the calculations of cost per delivery for vasectomy reversal vs. sperm
retrieval/ICSI, under a wide variety of initial assumptions, it is clear that vasectomy reversal is
associated with a considerably lower cost per delivery and higher delivery rates [85,118,199,200].
Sperm retrieval and ICSI must yield an 81% pregnancy rate per cycle to achieve equal costs to
vasectomy reversal.

5.8.4.Summary of evidence and recommendations for male
contraception

Summary of evidence

LE

Vasectomy meets best the
criteria for male contribution to permanent contraception, with regard to efficacy, safety and side effects.

1a

All available data indicate
that vasectomy is not associated with any serious, long-term side-effects.

1b

Microsurgical vasectomy
reversal is a low-risk and cost-effective method of restoring fertility.

1a

Methods of male contraception
other than vasectomy are associated with high failure rates or are still experimental (e.g.,
hormonal approach).

3

Recommendations

Strength
rating

Use cauterisation and
fascial interposition as they are the most effective techniques for the prevention of early
recanalisation.

Strong

Inform patients
seeking vasectomy about the surgical technique, risk of failure, potential irreversibility,
the need for post-procedure contraception until clearance, and the risk of
complications.

Strong

In order to achieve
pregnancy, microsurgical epididymal sperm aspiration/percutaneous epididymal sperm
aspiration/testicular sperm extraction - together with intracytoplasmic sperm injection is a
second-line option for men who decline a vasectomy reversal and those with failed vasectomy
reversal surgery.

Weak

5.9.Male accessory gland infections and infertility

5.9.1.Introduction

Infections of the male urogenital tract are potentially curable causes of male
infertility [125,201,202].
The WHO considers urethritis, prostatitis, orchitis and epididymitis to be male accessory gland
infections (MAGIs) [125].
However, specific data are not available to confirm that these diseases have a negative influence on
sperm quality and male fertility in general.

5.9.2.2.Microbiological findings

After exclusion of urethritis and bladder infection, >106 peroxidase-positive white blood-cells (WBCs) per millilitre of
ejaculate indicate an inflammatory process. In this case, a culture should be performed for common
urinary tract pathogens. A concentration of >103 cfu/mL urinary
tract pathogens in the ejaculate is indicative of significant bacteriospermia. The sampling time can
influence the positive rate of micro-organisms in semen and the frequency of isolation of different
strains [203].
The ideal diagnostic test for Chlamydia trachomatis in semen
has not yet been established [204].
In contrast to serological findings in women, antibody tests for C. trachomatis
in seminal plasma are not indicative if no type-specific methods are used [198].
Ureaplasma urealyticum is pathogenic only in high
concentrations (>103 cfu/mL ejaculate). No more than 10% of
samples analysed for ureaplasma exceed this concentration [205].
Normal colonisation of the urethra hampers the clarification of mycoplasma-associated urogenital
infections, using samples such as the ejaculate [206].

5.9.2.3.White blood cells

The clinical significance of an increased concentration of leukocytes in the
ejaculate is controversial [207].
Infection is indicated only by an increased level of leukocytes. Although leukocytospermia is a sign
of inflammation, it is not necessarily associated with bacterial or viral infections [208].
According to the WHO classification, leukocytospermia is defined as >106
WBCs/mL. Only two studies have analysed alterations of WBCs in the ejaculate of patients with proven
prostatitis [209,210].
Both studies found more leukocytes in men with prostatitis compared to those without inflammation
(CPPS, type NIH 3B).

5.9.2.4.Sperm quality

The deleterious effects of chronic prostatitis (CP/CPPS) on sperm density, motility
and morphology has been shown in a recent systematic review based on case-controlled studies [211].

5.9.2.5.Seminal plasma alterations

Seminal plasma elastase is a biochemical indicator of polymorphonuclear lymphocyte
activity in the ejaculate [202,212,213],
with a suggested cut-off level of approximately 600 ng/mL [202].
Various cytokines are involved in inflammation and can influence sperm function. Several studies
have investigated the association between interleukin (IL) concentration, leukocytes, and sperm
function [214-216],
but no correlations have been found. The prostate is the main site of origin of IL-6 and IL-8 in the
seminal plasma. Cytokines, especially IL-6, play an important role in the male accessory gland
inflammatory process [217].
However, elevated cytokine levels do not depend on the number of leukocytes in expressed prostatic
secretion (EPS) [218].

Only antibiotic therapy of chronic bacterial prostatitis (NIH II according to the
classification) has provided symptomatic relief, eradication of microorganisms, and a decrease in
cellular and humoral inflammatory parameters in urogenital secretions. Although antibiotics might
improve sperm quality [223],
there is no evidence that treatment of chronic prostatitis increases the probability of natural
conception [202,224].

5.9.3.Epididymitis

Inflammation of the epididymis causes unilateral pain and swelling, usually with
acute onset. Among sexually active men < 35 years of age, epididymitis is most often caused by
C. trachomatis or Neisseria gonorrhea [225,226].
Sexually transmitted epididymitis is usually accompanied by urethritis. Non-sexually transmitted
epididymitis is associated with urinary tract infection and occurs more often in men aged > 35
years [227].

5.9.3.1.Diagnostic evaluation

5.9.3.1.1.Ejaculate analysis

Ejaculate analysis according to WHO criteria, might indicate persistent
inflammatory activity. Transiently decreased sperm counts and forward motility are observed [225,228,229].
Semen culture might help to identify pathogenic micro-organisms. Development of stenosis in the
epididymal duct, reduction of sperm count, and azoospermia are more important in the follow-up of
bilateral epididymitis (see Chapter 5.3).

Patients with epididymitis known or suspected to be caused by N. gonorrhoeae or C. trachomatis must be told to refer their sexual partners for evaluation and treatment [230].

5.9.4.Summary of evidence and recommendation for male accessory gland infections

Summary of evidence

LE

Urethritis and prostatitis are
not clearly associated with impaired natural conception.

3

Antibiotic treatment often
only eradicates micro-organisms; it has no positive effect on inflammatory alterations and cannot reverse functional deficits and
anatomical dysfunction.

2a

Although antibiotic treatment
for MAGI might provide improvement in sperm quality, it does not necessarily enhance the probability of conception.

2a

Recommendation

Strength
rating

Instruct patients
with epididymitis that is known or suspected to be caused byN. gonorrhoeae or C. trachomatis
to refer their sexual partners for evaluation and treatment.

Strong

5.10.Germ cell malignancy and testicular
microcalcification

5.10.1.Germ cell malignancy and male infertility

Testicular germ cell tumour (TGCT) is the most common malignancy in Caucasian men
aged 15-40 years, and affects approximately 1% of sub-fertile men. The lifetime risk of TGCT varies
between ethnic groups and countries. The highest annual incidence of TGCT occurs in Caucasians, and
varies from 10/100,000 (e.g., in Denmark and Norway) to 2/100,000 (e.g., in Finland and the Baltic
countries). Generally, seminomas and nonseminomas are preceded by CIS, and untreated ITGCNU will
eventually progress to invasive cancer [231,232].
The most convincing evidence for a general decline in male reproductive health is the increase in
testicular cancer seen in western countries [233,234].
In almost all countries with reliable cancer registers, the incidence of testicular cancer has
increased [74,235].
Cryptorchidism and hypospadias are associated with an increased risk of testicular cancer; men with
cryptorchidism and/or hypospadias are over-represented among patients with testicular cancer. Men
with dysgenic testes have an increased risk of developing testicular cancer in adulthood. These
cancers arise from premalignant gonocytes or CIS cells [236].
Testicular microcalcification (TM), seen on US, can be associated with GCT and CIS of the testes.

5.10.2.Testicular germ cell cancer and reproductive function

Men with TGCT have decreased semen quality, even before cancer is diagnosed with
azoospermia in about 5–8% [237].
Semen cryopreservation before orchidectomy is recommended (see Chapter 5.12). In case of
azoospermia, testicular sperm may be recovered to safeguard the patient’s fertility (Onco-TESE) [238].
Principles in Onco-TESE do not differ from the conductance of TESE for other reasons and a
multifocal approach should be employed for the contralateral side.

Treatment of TGCT can result in additional impairment of semen quality [239]
and increased sperm aneuploidy at least up to two years following gonadotoxic therapy [240].
In addition to spermatogenic failure, patients with TGCT have Leydig cell dysfunction, even in the
contralateral testis [241].
The risk of hypogonadism may therefore be increased in men treated for TGCT. The measurement of
pre-treatment levels of testosterone, SHBG, LH and oestradiol might help to anticipate
post-treatment hypogonadism. Men who have had TGCT and have low normal androgen levels should
receive long-term follow-up because they are at risk of developing hypogonadism as a result of an
age-related decrease in testosterone production [242].
The risk of hypogonadism is most pronounced in TGCT patients treated with more than three cycles of
chemotherapy or irradiation of retroperitoneal lymph nodes. However, this risk is greatest at six to
twelve months post-treatment. This suggests there may be some improvement in Leydig cell function,
and why it is reasonable to expect initiation of androgen replacement, until the patient shows
continuous signs of testosterone deficiency, even at two years follow-up [231]. The risk of low libido and erectile dysfunction is also increased in TGCT patients [243].

5.10.3.Testicular microcalcification (TM)

Microcalcification inside the testicular parenchyma can be found in 0.6-9% of men
referred for testicular US [244,245].
Although the true incidence of microcalcification in the general population is unknown, it is
probably rare. However, US findings of TM are common in men with TGCT, cryptorchidism, testicular
dysgenesis, infertility, testicular torsion and atrophy, Klinefelter’s syndrome, hypogonadism, male
pseudoherma-phroditism, varicocele, epididymal cysts, pulmonary microcalcification, and
non-Hodgkin’s lymphoma. The incidence reported seems to be higher with high-frequency US machines
[246].
The relationship between TM and infertility is unclear, but probably relates to dysgenesis of the
testes, with degenerate cells being sloughed inside an obstructed seminiferous tubule and failure of
the Sertoli cells to phagocytose the debris. Subsequently, calcification occurs. Testicular
microcalcification is found in testes at risk of malignant development. The reported incidence of TM
in men with TGCT is 6-46% [247-249].
TM should therefore be considered premalignant. Testicular biopsies from men with TM have found a
higher prevalence of CIS, especially in those with bilateral microcalcification [250].
However, TM is found most often in men with a benign testicular condition and the microcalcification
itself is not malignant. Further investigation of the association between TM and CIS will require
testicular biopsies in large series of men without signs of TGCT. However, available data indicate
that men in whom TM is found by US, and who have an increased risk of TGCT, should be offered
testicular biopsy for detection of CIS. The list of high-risk patients includes men with infertility
and bilateral TM, atrophic testes, undescended testes, a history of TGCT, and contralateral TM [234].

Perform testicular
biopsy for men with TM, who belong to one of the following high-risk groups: spermatogenic
failure, bilateral TM, atrophic testes (less than 12cc), history of undescended testes and
TGCT.

Strong

If there are
suspicious findings on physical examination or ultrasound in patients with TM and associated
lesions, perform surgical exploration with testicular biopsy or orchidectomy.

Strong

Follow men with TGCT
because they are at increased risk of developing hypogonadism and sexual dysfunction.

Strong

5.11.Disorders of ejaculation

Disorders of ejaculation are uncommon, but important causes of male
infertility.

5.11.1.Classification and aetiology

5.11.1.1.Anejaculation

Anejaculation involves complete absence of antegrade or retrograde ejaculation. It
is caused by failure of semen emission from the seminal vesicles, prostate and ejaculatory ducts
into the urethra [251].
True anejaculation is usually associated with a normal orgasmic sensation and is always associated
with central or peripheral nervous system dysfunction or with drugs [252]
(Table 6).

5.11.1.2.Anorgasmia

Anorgasmia is the inability to reach orgasm and can give rise to anejaculation.
Anorgasmia is often a primary condition and its cause is usually psychological.

5.11.1.3.Delayed ejaculation

In delayed ejaculation, abnormal stimulation of the erect penis is needed to
achieve orgasm with ejaculation [251].
Delayed ejaculation can be considered a mild form of anorgasmia. The causes of delayed ejaculation
can be psychological, organic (e.g. incomplete spinal cord lesion [253]
or iatrogenic penile nerve damage [254]),
or pharmacological (e.g. selective serotonin re-uptake inhibitors (SSRIs), antihypertensives, or
antipsychotics) [255].

5.11.1.4.Retrograde ejaculation

Retrograde ejaculation is the total, or sometimes partial, absence of antegrade
ejaculation as a result of semen passing backwards through the bladder neck into the bladder.
Patients experience a normal or decreased orgasmic sensation. The causes of retrograde ejaculation
can be divided into neurogenic, pharmacological, urethral, or bladder neck incompetence (Table
6).

5.11.1.5.Asthenic ejaculation

Asthenic ejaculation is characterised by an altered propulsive phase, with a normal
emission phase [255].
The orgasmic sensation is reduced and the typically rhythmical contractions associated with
ejaculation are missing. Asthenic ejaculation does not usually affect semen quality.

5.11.1.6.Premature ejaculation

The International Society for Sexual Medicine (ISSM) has adopted the first
evidence-based definition of lifelong premature ejaculation (PE): “Premature ejaculation is a male
sexual dysfunction characterised by ejaculation which always or nearly always occurs prior to or
within about one minute of vaginal penetration; and inability to delay ejaculation on all or nearly
all vaginal penetrations; and negative personal consequences, such as distress, bother, frustration
and/or the avoidance of sexual intimacy”. Premature ejaculation may be strictly organic (e.g.,
prostatitis-related) or psychogenic, partner-related or non-selective, and can be associated with
erectile dysfunction. It does not impair fertility, provided intravaginal ejaculation occurs.

5.11.2.Diagnostic evaluation

Diagnostic management includes the following recommended procedures.

5.11.2.1.Clinical history

The patient must be carefully checked for diabetes, neuropathy, trauma, urogenital
infection, previous surgery, and medication. Particular attention must be paid to the
characteristics of micturition and ejaculation (presence of nocturnal emission, ejaculatory ability
in given circumstances, and primary or acquired disorder), as well as to psychosexual aspects.

5.11.2.2.Physical examination

Genital and rectal examinations are conducted, including evaluation of the
prostate, bulbocavernosus reflex and anal sphincter tone.

5.11.2.3.Post-ejaculatory urinalysis

Post-ejaculatory urinalysis of centrifuged urine can be used to determine if there
is total or partial retrograde ejaculation.

5.11.3.Disease management

Infertility caused by disorders of ejaculation is seldom treated on the basis of
aetiology. Treatment usually involves retrieval of spermatozoa for use in assisted reproduction
techniques (ARTs). The following aspects must be considered when selecting treatment:

age of patient and his partner;

psychological problems of the patient and his partner;

couple’s willingness and acceptance of different fertility procedures;

associated pathology;

psychosexual counselling.

5.11.3.1.Aetiological treatment

If possible, any pharmacological treatment that is interfering with ejaculation
should be stopped. In painful ejaculation, tamsulosin can be administered during antidepressant
treatment [258].
Treatment should be given for urogenital infections (i.e., in case of painful ejaculation) [257].
Dapoxetin is an SSRI that has been introduced for the therapy of PE [259],
because it appears that PE is related to serotonin levels. Psychotherapy is usually not very
effective.

5.11.3.2.Symptomatic treatment

5.11.3.2.1.Premature ejaculation

Premature ejaculation can be treated with the SSRI dapoxetine or topical
anaesthetic agents to increase intravaginal ejaculation latency time, behavioural therapy, and/or
psychotherapy.

5.11.3.2.2.Retrograde
ejaculation

In the absence of spinal cord injury, anatomical anomalies of the urethra, or
pharmacological agents, drug treatment must be used to induce antegrade ejaculation (Table 7).
Alternatively, the patient can be encouraged to ejaculate when his bladder is full to increase
bladder neck closure [260].

Sperm collection from post-orgasmic urine for use in ART is recommended if:

drug treatment is ineffective or intolerable as a result of side-effects;

the patient has a spinal cord injury;

drug therapy inducing retrograde ejaculation cannot be interrupted.

If the biological sperm preparation is not of sufficient quality for intrauterine
insemination, the couple must undergo in vitro reproductive procedures (e.g. ICSI). In the case of
insufficient drug therapy, testicular (TESE or PESA) or epididymal (MESA) sperm retrieval techniques
can be used for assisted reproduction.

5.11.3.2.3.Anejaculation

Drug treatment for anejaculation caused by lymphadenectomy and neuropathy, or
psychosexual therapy for anorgasmia is not very effective. In all these cases, and in men who have a
spinal cord injury, vibrostimulation (i.e., application of a vibrator to the penis) is first-line
therapy. In anejaculation, vibrostimulation evokes the ejaculation reflex [265],
which requires an intact lumbosacral spinal cord segment. If the quality of semen is poor, or
ejaculation is retrograde, the couple may enter an IVF programme. If vibrostimulation has failed,
electro-ejaculation can be the therapy of choice [266].
When electro-ejaculation fails or cannot be carried out, sperm can be retrieved from the seminal
ducts by aspiration from the vas deferens [267]
(see Chapter 5.3) or seminal tract washout [268].
TESE can then be used [257,269].
Anejaculation following either surgery for testicular cancer or total mesorectal excision can be
prevented using monolateral lymphadenectomy or autonomic nerve preservation [269],
respectively.

5.11.4.Summary of evidence and recommendation for disorders of ejaculation

Summary of evidence

LE

Ejaculation disorders can be
treated using a wide range of drugs and physical stimulation (eg vibratory stimulation),
with a high level of efficacy.

3

Pharmacotherapy includes
either dapoxetine on demand (a short-acting SSRI that is the only approved pharmacological treatment for PE) or other off-label
antidepressants, i.e. daily SSRIs and clomipramine, that are not amenable to on-demand dosing.
Alternatively use topical anaesthetics (LE: 1b) or tramadol (LE: 2a).

1a

In men with spinal cord
injury, vibrostimulation and/or electro-ejaculation are effective methods of sperm retrieval.

5.12.Semen cryopreservation

Cryopreservation is the storage of biological material at sub-zero temperatures
[e.g., - 80 or -196°C (the boiling point of liquid nitrogen)], at which the biochemical processes of
cell metabolism are slowed or interrupted. At -196°C, the biochemical reactions that lead to cell
death are stopped.

5.12.1.Indications for storage

Storage of sperm is available in many clinics for the following indications:

Before potentially sterilising chemotherapy or radiotherapy for cancer (onco-TESE) or for
non-malignant diseases [270].
In adolescent patients semen cryopreservation and/or surgical retrieval can be offered [271].
In prepubertal boys, testicular tissue banking can be undertaken but is currently experimental [272];

Before surgery that might interfere with fertility (e.g. bladder neck surgery in a younger man
or removal of a testicle in a man with testicular malignancy, or before vasectomy or transgender
surgery);

For men with progressive decrease in semen quality as a result of diseases that have an
associated risk of subsequent azoospermia (i.e., pituitary macroadenoma, craniopharyngioma,
empty sella syndrome, chronic nephropathy, uncontrolled diabetes mellitus, and multiple
sclerosis);

For men with paraplegia when sperm have been obtained by electro-ejaculation or obtained by
penile vibratory stimulation;

For men with psychogenic anejaculation, after sperm have been obtained either by
electro-ejaculation or a sperm retrieval procedure;

After gonadotropin treatment has induced spermatogenesis in men with hypogonadotropic
hypogonadism;

For men with NOA, the chance of finding sperm using micro-TESE is ~50%.

Cryopreservation can be used for sperm collected through TESE, avoiding repeated
sperm retrieval procedures and unnecessary hyperstimulation of the female partner:

in any situation in which sperm have been obtained by a sperm retrieval procedure (e.g., after
failed vasectomy reversal, or in some cases of epididymal obstruction not amenable to surgery);

for storage of donor sperm, because cryopreservation reduces the risk of transmission of
infection from sperm donors. According to the European directives 2004/23 EC and 2006/17 EC
fresh sperm are no longer to be used for non-partner donations.

5.12.2.Precautions and techniques

5.12.2.1.Freezing and thawing process

The cryopreservation techniques currently used are not yet optimal because damage
occurs to cells during cryopreservation and prolonged storage. Most damage occurs during freezing
and thawing. Major causes of damage during freezing are ice crystal formation and cell dehydration,
which disrupt the cell wall and intracellular organelles. Sperm morphology, motility and vitality
decrease significantly after thawing, and cryopreservation increases the damage done to sperm DNA
[273-276].
Further damage can be caused by contamination of samples with micro-organisms and high levels of
superoxide radicals [277,278].
To reduce ice crystal formation, a cryopreservation solution is added before freezing. Various
cryopreservation solutions are available commercially, most of which contain varying proportions of
glycerol and albumin. After freezing, the samples are immersed in liquid nitrogen.

Several techniques have been developed to try to reduce damage caused by freezing
and thawing, including:

one-step freezing method [279,280]:
sample is held in the vapour phase for ten minutes before being plunged into liquid nitrogen;

slow or multi-step method [281]:
sample is gradually cooled in the vapour phase for approximately 40 minutes. A programmable
automatic freezing machine, which is pre-set to cool at a rate of 1-10°C per minute is used.

The method available depends on the resources of the laboratory. Whichever freezing
technique is used, it should be tested using donor sperm and post-thaw examination, and should
regularly undergo a quality-control programme. The likelihood of sperm survival decreases with
repeated freezing and thawing. The maximum viable storage time for human sperm is not known.

5.12.2.2.Cryopreservation of small numbers of sperm

Standard cryopreservation in straws is an efficient way of storing large numbers of
sperm (e.g., for a donor insemination programme). However, in micro-TESE, few sperm might be
obtained, and the choice is either to freeze testicular tissue and find sperm after thawing the
tissue, or to freeze small numbers of sperm. If sperm are frozen in straws, it can be difficult to
find any sperm after thawing. Instead, the sperm should be frozen in a pellet [282]
or in a container [283].

5.12.2.3.Testing for infections and preventing
cross-contamination

Sperm storage in straws is used extensively. Large numbers of straws are stored in
canisters, with the straws being bathed in a pool of liquid nitrogen. Microbial contamination of the
pool of liquid nitrogen results in contamination of the outside of all the straws [284].
The most widely used safeguard is to use so-called high security closed straws. According to the
European directives 2004/23 and 2006/17, samples should be tested for hepatitis B and C and human
immunodeficiency virus (HIV). In case of non-partner donation, samples are also tested for C. trachomatis (by Nucleic Acid Testing [NAT]) and syphilis,
as well as genetics, that is, karyotype and most prevalent genetic disorders in the population
to which the non-partner donor belongs. Until the test results are known, samples must be stored
in an individual quarantine vessel (separate storage). If open straws are used (e.g., for
vitrification purposes) some laboratories use the additional safeguard of doublewrapping the straws
before freezing, although this is more costly. Some centres carry out cytomegalovirus testing and
store negative and positive samples separately. Considerable ethical issues surround the storage
of samples before cancer chemotherapy in men who are hepatitis-virus- or are HIV-positive. Few
clinics have separate storage facilities for HIV-positive samples. However, the success of
anti-retroviral treatment is increasing the number of HIV-positive men who may wish to store sperm.
There is also concern about HIV transmission to children conceived using HIV-positive sperm, because
sperm-washing techniques fail in ~5% of cases.

5.12.2.4.Fail-safe
precautions to prevent loss of stored materials

Any laboratory that undertakes long-term storage of human biological materials
should have procedures that guard against accidental loss of material caused by storage vessel
failure. This is particularly important for sperm stored before potentially sterilising cancer
chemotherapy, because these patients may not be able to obtain further sperm.

5.12.2.5.Orphan samples

In malignancy and some other situations, several years might pass before stored
samples are required. Inevitably, during this time, the owners of some samples might disappear or
die, leaving behind orphan samples for which the owner is no longer contactable. The duty of the
laboratory and the legal ownership of these samples can create considerable problems.

5.12.3.Biological aspects

Cryopreservation induces deterioration of semen quality. After the sample has been
thawed, motility [285]
and morphology [286,287]
are worsened, including mitochondrial acrosomal and sperm tail damage [262].
Sperm freezing decreases motility by 31% and mitochondrial activity by 36%, and causes morphological
disruption in 37% of sperm [280].
Motility is correlated best with IVF capacity of the thawed sample. Further improvement can be
achieved by selecting the subpopulation of sperm with the best motility and DNA integrity and
freezing these sperm in seminal plasma [282].

5.12.4.Summary of evidence and recommendations for semen cryopreservation

Summary of evidence

LE

The purpose of sperm
cryopreservation is to enable future ART procedures.

1b

Cryopreservation techniques
are not optimal, and future efforts are needed to improve the outcome of sperm banking.

3

Recommendations

Strength
rating

Offer
cryopreservation of semen to all men who are candidates for chemotherapy, radiation or
surgical interventions that might interfere with spermatogenesis or cause ejaculatory
disorders.

Strong

Offer simultaneous
sperm cryopreservation if testicular biopsies will be performed for fertility diagnosis.

Strong

If cryopreservation
is not available locally, inform patients about the possibility of visiting, or transferring
to a cryopreservation unit before therapy starts.

Strong

Take precautions to
prevent transmission of viral, sexually transmitted or any other infection by cryostored
materials from donor to recipient, and to prevent contamination of stored samples. These
precautions include testing of the patient and the use of rapid testing and quarantine of
samples until test results are known. Do not store samples from men who are positive for
hepatitis virus or HIV in the same container as samples from men who have been tested and
are free from infection.

7.Bruins M., et al. What is the
effectiveness and harm of medical and/or nutritional therapy on the pregnancy rate in couples with
idiopathic male infertility? PROSPERO: International prospective register of systematic reviews,
2016.

27.Ghanem, M., et al. Comparison of
the outcome of intracytoplasmic sperm injection in obstructive and non-obstructive azoospermia in
the first cycle: a report of case series and meta-analysis. Int J Androl, 2005. 28: 16.

31.Vernaeve, V., et al.
Intracytoplasmic sperm injection with testicular spermatozoa is less successful in men with
nonobstructive azoospermia than in men with obstructive azoospermia. Fertil Steril, 2003. 79: 529.

86.Zhang, F., et al. Partial
deletions are associated with an increased risk of complete deletion in AZFc: a new insight into the
role of partial AZFc deletions in male infertility. J Med Genet, 2007. 44: 437.

243.Skinner, R., et al.
Recommendations for gonadotoxicity surveillance in male childhood, adolescent, and young adult
cancer survivors: a report from the International Late Effects of Childhood Cancer Guideline
Harmonization Group in collaboration with the PanCareSurFup Consortium. Lancet Oncol, 2017. 18: e75.

7.CONFLICT OF INTEREST

All members of the EAU Male Infertility Guidelines working panel have provided
disclosure statements on all relationships that they have that might be perceived to be a potential
source of conflict of interest. Thisinformation is publically accessible through the European
Association of Urology website http://www.uroweb.org/guidelines/.
This document was developed with the financial support of the European Association of Urology. No
external sources of funding and support have been involved. The EAU is a non-profit organisation and
funding is limited to administrative assistance and travel and meeting expenses. No honoraria or
other reimbursements have been provided.

8.CITATION INFORMATION

The format in which to cite the EAU Guidelines will vary depending on the style
guide of the journal in which the citation appears. Accordingly, the number of authors or whether,
for instance, to include the publisher, location, or an ISBN number may vary.

The compilation of the complete Guidelines should be referenced as:EAU Guidelines. Edn. presented at the EAU Annual Congress Barcelona 2019. ISBN 978-94-92671-04-2.